CSER: South-Seq: DNA Sequencing for Newborn Nurseries in the South

SouthSeq, part of the Clinical Sequencing Evidence-Generating Research (CSER2) effort, aims to perform genome sequencing for infants in nurseries at hospitals in Alabama, Mississippi, Louisiana, and Kentucky. SouthSeq aims to sequence 600 newborn babies presenting with congenital anomalies, or other signs of a rare genetic disorder. The primary goals of SouthSeq are to provide early diagnoses to children with rare genetic conditions, to demonstrate the utility of genome sequencing as a frontline test with potential to improve intermediate and long-term clinical outcomes, and to equip non-genetics providers to deliver test results in order to facilitate the conduction of genome sequencing outside of major medical centers where patients may not have access to a genetics provider. SouthSeq also aims to ensure that genomic testing is applied across diverse communities; recruitment efforts focus on patients from rural and minority populations that have been historically under-represented in both medicine and genomics research. Sequencing and analysis for SouthSeq are being conducted at the HudsonAlpha Institute for Biotechnology in Huntsville, Alabama (https://www.hudsonalpha.org/). Enrollment of infants with signs of genetic disease is approved at five clinical sites, including nurseries at the University of Alabama at Birmingham, the University of Mississippi Medical Center, Woman's Hospital in Baton Rouge, Children's Hospital in New Orleans, and the University of Louisville. Both biological parents are enrolled when available so that follow-up testing can be performed to determine inheritance. Further, participant families may choose to opt-into return of secondary findings identified in the proband, which focus on pathogenic and likely pathogenic variation identified within ACMG SFv3.0 genes.
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For inclusion in this study as a proband, an infant must have been receiving care in the nursery or inpatient setting, e.g. surgical and/or cardiac intensive care unit during his/her first hospital admission, or the first 12 months of life, and must meet one of the following criteria:a pattern of congenital anomalies consistent with a genetic, i.e. syndromic cause, and for which the primary care team does not know of an obvious etiology. “Obvious etiology” refers to a genetic, infectious, or environmental cause that has been or can be rapidly confirmed by history and/or laboratory testing, e.g. Trisomy 21, TORCH infection, or fetal hydantoin exposure.a major medical condition, such as seizures, metabolic abnormality, or conjugated hyperbilirubinemia, for which the primary care team does not know of an obvious etiology. Again, “obvious etiology” refers to a genetic, infectious, or environmental cause that has been or can be rapidly confirmed by history and/or laboratory testing, e.g. intraventricular hemorrhage associated with significant prematurity, seizures associated with an inborn error of metabolism for which a molecular diagnosis can be confirmed.  Infants born deceased or those who expire soon after birth may also be enrolled as long as they meet the criteria outlined above. Infants who otherwise would have met inclusion criteria, but passed away during the time that SouthSeq was actively enrolling participants were also enrolled, provided that blood samples were available and parents consented to the study.  Individuals were excluded from the study if they had:a pattern of findings and/or abnormalities consistent with known or strong suspicion for a chromosomal aneuploidy (Ts13, 18, 21, Monosomy X);isolated anomalies known to have a low diagnostic yield for Mendelian causes, e.g. gastroschisis, hydronephrosis;a pattern of findings and/or abnormalities consistent with confirmed teratogenic exposures, e.g. hydantoin, valproate;a pattern of findings and/or abnormalities consistent with confirmed congenital infection, e.g. TORCH.Additional Comments:Patients with suspected Down syndrome or life-threatening whole chromosome aneuploidies in which acute clinical care depends on a diagnosis, e.g. Ts13 or Ts18, were not enrolled, but patients with congenital anomalies for which a clinical chromosomal microarray would otherwise be obtained were offered enrollment.Patients with a history of potential teratogenic exposures or congenital infection may have been eligible for inclusion if there are congenital anomalies and/or conditions that are not explained by the potential teratogen or infection. In this situation, one of the study investigators was consulted.“Pattern of findings and/or abnormalities” refers to established principles for medical genetics, in which general guidelines are “2 or major congenital anomalies”, “1 major and 2 or more minor anomalies”, “1 major anomaly and an unexplained major medical condition”, or “1 major anomaly and a first degree relative with the same anomaly”, with examples (not intended to be exhaustive) indicated below. As this is a research study, it was not intended to replace routine clinical care. Patients were also provided standard of care clinical genetics consultation, which may have included microarray/array CGH. If the array result was abnormal, the research team had the opportunity to decide if sequencing was appropriate. We intended to keep these criteria broad to allow for the enrollment of individuals with rare symptoms and avoid exclusion of those who might benefit from whole genome sequencing.Biological parents of the proband (infant admitted into the nursery) were also enrolled in the study, whether they were affected or unaffected with a rare disease, for the purpose of confirming inheritance of variants of interest. ]]>
February 2018: Enrollment of first participantFebruary 2019: Clinical trial beganJuly 2021: Enrollment completed (n=640 probands)]]>